The systematic wrapping of an axon by insulating myelin sheaths is a remarkable event in the development of the vertebrate central nervous system (CNS). Despite the importance of myelin for the rapid conduction of action potentials, little is known about its molecular mechanism. In this proposal, we will focus on understanding the transcriptional control of CNS myelination. Although several transcription factors have been identified that are required for the generation of oligodendrocytes and their precursor cells, the transcriptional mechanisms that control expression of CNS myelin genes are still poorly understood. In a recent screen for transcripts that display cell-type specific expression within the CNS, we identified an uncharacterized putative transcription factor, gene model 98 (GM98), which is expressed specifically by postmitotic oligodendrocytes (OLs). We have demonstrated that GM98 is a nuclear protein and that its mRNA and protein are highly expressed specifically by OLs, but not by OL precursor cells or other CNS cell types. In vitro, we have found that the expression of GM98 is both necessary and sufficient for oligodendrocyte progenitors to differentiate into postmitotic oligodendrocytes expressing myelin genes. In this proposal we will further characterize the role of GM98 as a transcriptional regulator in oligodendrocyte generation and myelination, identify GM98 binding partners, and investigate the genomic regions and genes that are targeted by GM98. These experiments will provide a better understanding of the molecular mechanisms that control CNS myelination. Understanding how myelination is regulated may suggest new ways of enhancing remyelination after injury or diseases such as optic neuritis and Multiple Sclerosis. PUBLIC HEALTH RELEVANCE: Demyelination of CNS axons can cause failure of action potential conduction leading to devastating neurological dysfunctions in Multiple Sclerosis and other demyelinating diseases. Understanding how myelin genes are regulated may prove vital for restoring myelination in demyelinating diseases. These studies have the potential to shed new light on how myelination normally occurs and how myelin can be repaired in many different neurological diseases.